Funxion Plus Mechanism of Action

Pharmacology: Pharmacodynamics: Pregabalin: Pregabalin is an anticonvulsant that is structurally related to the inhibitory central nervous system (CNS) neurotransmitter gamma aminobutyric acid (GABA). Although pregabalin was developed as a structural analog of GABA, the drug does not bind directly to GABA_A, GABA_B, or benzodiazepine receptors; does not augment GABA_A responses in cultured neurons; and does not alter brain concentrations of GABA in rats or affect GABA uptake or degradation. However, in cultured neurons, prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport.
Pregabalin binds with high affinity to the α₂-δ site (an auxiliary subunit of voltage-gated calcium channels) in CNS tissues. Although the exact mechanism of action of pregabalin has not been elucidated, binding to the α₂-δ subunit may be involved in pregabalin's anticonvulsant effect.
Mecobalamin: Mecobalamin is an active form of Vitamin B₁₂. It regenerates damaged neuron by serving as a cofactor in the methionine synthase reaction. Mecobalamin transfers its methyl group to homocysteine to yield methionine. Methionine is a precursor of S-adenosylmethionine (SAMe), the principal transmethylating agent in the body. SAMe is also involved in the synthesis of myelin basic protein. Thus, mecobalamin helps in maintaining the integrity of the myelin sheath, the protective coating that surrounds the nerve fibers.
Pharmacokinetics: Pregabalin: Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within one hour after both single and multiple dose administration. Pregabalin oral bioavailability is estimated to be ≥90% and is independent of dose. Maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) values increase proportionally after single- and multiple-dose administration. After repeated administration, steady state is achieved within 24 to 48 hours. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in C_max by approximately 25 to 30% and a delay in T_max to approximately 2.5 hours. However, administration of pregabalin with food has no clinically significant effect on the extent of pregabalin bioavailability.
At clinical doses of 150 to 600 mg per day, the average steady-state plasma pregabalin concentrations were approximately 1.5 and 6 mcg/mL, respectively. Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for pregabalin is low (< 20%). Multiple dose pharmacokinetics are predictable from single-dose data.
The apparent volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin is not bound to plasma proteins. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. In animal models, pregabalin has been shown to cross the blood brain barrier.
Pregabalin undergoes negligible metabolism in human. After a dose of radiolabelled pregabalin, approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, there was no indication of racemization of pregabalin S-enantiomer to the R-enantiomer.
In vitro drug metabolism showed that pregabalin, at concentrations which were generally 10-fold greater than observed in Phase 2/3 clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2D6, CYP2E1, and CYP3A4 enzyme systems.
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. Renal clearance (CL_cr) derived from Phase I studies was 73 mL/min. Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance.
Special Population: Renal impairment: Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (after a four-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%). Because renal elimination is the major elimination pathway, dosage reduction in patients with renal impairment and dosage supplementation after hemodialysis is necessary.
Hepatic impairment: Since pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma concentrations.
Elderly: Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with decreases in creatinine clearance associated with increasing age. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.
Mecobalamin: Vitamin B₁₂ is a collective term for all cobalt-containing, bioactive members of the cobalamin family. The principal cobalamins are cyanocobalamin, hydroxocobalamin and the other two coenzyme forms of vitamin B₁₂, which are mecobalamin and 5-deoxyadenosylcobalamin (adenosylcobalamin). Vitamin B₁₂ binds and forms a complex with R protein (also known as haptocorrin), a protein secreted by the salivary glands and gastric mucosa that may protect vitamin B₁₂ as it travels through the stomach and into the small intestine. Haptocorrins have high affinity for vitamin B₁₂ in acidic condition; thus, binding occurs in the stomach. B₁₂-haptocorrin complexes are partially degraded by pancreatic proteases through hydrolysis in the small intestine in order to release B₁₂. The released B₁₂ will bind to intrinsic factor (IF), a 45-kDa glycoprotein secreted by the gastric parietal cells. Sufficient IF is released following a meal to bind two to four micrograms of vitamin B₁₂.
Absorption of vitamin B₁₂ occurs via two mechanisms: passive diffusion and active or physiological absorption. Passive diffusion occurs throughout the gastrointestinal tract. About one percent of any given dose of vitamin B₁₂ is absorbed through this mechanism. On the other hand, active or physiological absorption occurs when the B₁₂-IF complex is absorbed via a 460-kDa receptor called cubilin located in the distal ileum of the small intestine. Cubilin reacts with a second protein called amnionless (AMN), which is needed for the apical localization of cubilin in polarized cells. The B₁₂-IF complex binds to cubilin in the presence of Ca²⁺ and the internalized in the late endosomes through receptor-mediated endocytosis. The late endosomes then fuse with lysosomes resulting to the degradation of IF and the release of the vitamin B₁₂ into the cytosol. The released vitamin B₁₂ traverses the endothelial cell and enters the portal circulation. The process of vitamin B₁₂ absorption across the gut epithelium takes about three to four hours. The refractory period to restore unbound cubilin density and the maximal absorptive capacity is about six hours.
The physiological absorption mechanism can become saturated with relatively small amounts of oral vitamin B₁₂; thus, increased vitamin B₁₂ intake increases its total absorption, but the absorption efficiency of the vitamin decreases with increased dosage. About 50% of a vitamin B will be absorbed for doses of three micrograms or less, while percent absorption gradually decreases for doses greater than three micrograms. The maximum amount that can be absorbed from a given dose of vitamin B is approximately 1.5 mcg.
Vitamin B₁₂ absorption can be impaired by the following: absence or removal of the ileum or stomach, overgrowth of bacteria in the stomach, infestation with the tapeworm Diphyllobothrium latum, reduction of gastric acid production due to prolonged use of gastric acid inhibitors, malabsorption syndrome, disease or abnormality of the gut, atrophic gastritis or the lack of R protein, pancreatic enzymes or IF.
Recent evidences suggest that the released vitamin B₁₂ exits the enterocyte via the multidrug resistance protein 1 (MRP1/ABCC1) before forming a complex with transcobalamin in the blood. Transcobalamin is a 45.5 kDa β-globulin protein synthesized in the endothelial cells, enterocytes, liver and macrophages. The transcobalamin-vitamin B₁₂ complex is taken up in the tissues via receptor-mediated endocytosis. Transcobalamin delivers vitamin B₁₂ to the portal circulation and eventually to the liver, where 50% of the vitamin is taken up and stored. The remainder goes to the systemic circulation to be transported to the other tissues of the body.
The transcobalamin-vitamin B₁₂ complex is intracellularly degraded by lysosomal proteases to yield hydroxycob(III)alamin. In the cytosol, hydroxycob(III)alamin is reduced to cob(I)alamin, which is then methylated to the methylcob(III)alamin after binding to methionine synthase. Mecobalamin is the principal circulating form of vitamin B₁₂.
Vitamin B₁₂ is excreted in the bile. Its reabsorption via enterohepatic circulation requires the IF. Some of the B₁₂ secreted in the bile and unabsorbed oral B₁₂ is excreted in the feces. A small fraction of the dose is excreted in the urine, most of it in the first eight hours.